Role of Sox2 in Stress Adaptations to Ovarian Cancer Anchorage Independence

项目摘要 晚期卵巢癌的特点是由于腹膜腔中的转移性扩散而导致患者存活率差。 腹膜中的恶性腹水中含有肿瘤细胞，这些肿瘤细胞表现出对锚定独立存活的适应性 是跨体腔转移所必需的。因此，定义支持锚定的关键适应信号 腹水中的独立存活将导致控制卵巢癌相关死亡率的新方法。 我们最近发现Sox 2，一个关键的发育基因，作为锚定独立的重要调节因子， 生存Sox 2在癌症中的重要性被先前关于Sox 2在癌症干细胞中的功能的报道所强调 与患者生存率低的关系。奇怪的是，虽然接近75%的卵巢肿瘤显示SOX 2基因 拷贝数增加，Sox 2表达与肿瘤中的这种SOX 2扩增无关。意义 因此，SOX 2扩增与卵巢癌进展病因学的关系仍然难以捉摸。我们现在发现， 在卵巢癌中，Sox 2在失去附着时以上下文依赖的方式显著升高， 这是锚定独立生存所必需的。我们已经确定了Sox 2之前未探索的功能， 线粒体功能的主要调节者，在锚定独立性中的重要生存适应。Sox2 促进线粒体呼吸和线粒体电子传递链所需基因的表达 转录和翻译，以及抗氧化功能，包括锰超氧化物歧化酶，SOD 2。 虽然Sox 2最确定的作用是在发育过程中的谱系特化，但Sox 2 在卵巢癌中调节并促进转移期间的存活率在很大程度上是未知的。因此，我们的目标 在此将Sox 2定义为线粒体控制应激反应途径的汇聚点， 使用体外和体内方法的组合检测卵巢癌转移。完成这些 目的：1）在表观遗传背景下，定义Sox 2在锚定独立性下的调控 调节和代谢和氧化还原应激与损失的附件; 2）描绘的机制， 其中Sox 2作为线粒体功能和质量控制的关键调节剂;以及3）确定 Sox 2驱动的线粒体功能的锚定非依赖性生存和转移。我们的研究将 为Sox 2在卵巢癌中的动态调节和作用提供了重要的新知识。定义 Sox 2-线粒体轴是卵巢癌非锚定生存和转移的关键适应 这将是确定卵巢癌的关键应激适应的重要一步，可以作为治疗的目标。

PROJECT SUMMARY Late stage ovarian cancer is marked by poor patient survival due to metastatic spread in the peritoneal cavity. Malignant ascites in the peritoneum harbor tumor cells that exhibit adaptability to anchorage independent survival required for transcoelomic metastasis. Thus, defining key adaptation signals that support anchorage independent survival in the ascites will result in new approaches to control ovarian cancer associated mortality. We recently uncovered Sox2, a key developmental gene, as an important regulator of anchorage independent survival. Sox2’s significance in cancer is underscored by prior reports on Sox2 functions in cancer stem cells and associations with poor patient survival. Curiously, while close to 75% of ovarian tumors display SOX2 gene copy number gain, Sox2 expression does not correlate with this SOX2 amplification in tumors. The significance of SOX2 amplification to the etiology of ovarian cancer progression hence remains elusive. We now find that Sox2 is significantly elevated in a context-dependent manner in ovarian cancer upon loss of attachment and necessary for anchorage-independent survival. We have identified a previously unexplored function of Sox2 as a master regulator of mitochondrial function, an important survival adaptation in anchorage independence. Sox2 promotes mitochondrial respiration and expression of genes required for mitochondrial electron transport chain transcription and translation, and antioxidant function, including the manganese superoxide dismutase, Sod2. While Sox2’s most established role is in lineage specification during development, mechanisms by which Sox2 is regulated in ovarian cancer and promotes survival during metastasis are largely unknown. Thus, our objectives here are to define Sox2 as a convergence point of stress response pathways for mitochondrial control during ovarian cancer metastasis using a combination of in vitro and in vivo approaches. To accomplish these objectives, we will: 1) Define regulation of Sox2 under anchorage independence in the context of epigenetic regulation and metabolic and redox stress associated with loss of attachment; 2) Delineate the mechanisms by which Sox2 acts as a key regulator of mitochondrial function and quality control; and 3) Determine the necessity of Sox2-driven mitochondrial function for anchorage independent survival and metastasis. Our studies will provide significant new knowledge on the dynamic regulation and role of Sox2 in ovarian cancer. Defining the Sox2-mitochondrial axis as a key adaptation for ovarian cancer anchorage-independent survival and metastasis will be a major step in identifying key stress adaptations of ovarian cancer that can be targeted therapeutically.